Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition
Targeting NAD+ salvage pathway induces autophagy in multiple myeloma cells via mTORC1 and extracellular signal-regulated kinase (ERK1/2) inhibition
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DOI：
10.1182/blood-2012-03-416776
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发表时间：
2012-10-25
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
Cea, Michele;Cagnetta, Antonia;Anderson, Kenneth C.
恶性细胞具有比正常细胞更高的烟酰胺腺嘌呤二核苷酸（NAD（+））周转率，使得这种生物合成途径成为癌症治疗的有吸引力的靶点。在这里，我们研究了参与NAD（+）合成的限速酶Nampt在多发性骨髓瘤（MM）中的生物学作用。Nampt特异性化学抑制剂FK 866在MM细胞系和患者MM细胞中触发细胞毒性，但在正常供体以及MM患者PBMC中不触发细胞毒性。重要的是，FK 866以剂量依赖性方式在对传统和新型抗MM治疗耐药的MM细胞中引发细胞毒性，并克服细胞因子（IL-6、IGF-1）和骨髓基质细胞的保护作用。通过RNAi敲低Nampt证实了其在维持MM细胞活力和细胞内NAD（+）储存中的关键作用。有趣的是，FK 866的细胞毒性引发自噬，但不引发凋亡。自噬介导的FK 866 MM细胞毒性的转录依赖性（TFEB）和非依赖性（PI 3 K/mTORC 1）激活。最后，FK 866在异种移植物-小鼠MM模型中表现出显著的抗MM活性，与肿瘤细胞中ERK 1/2磷酸化和LC 3蛋白水解裂解的下调相关。因此，我们的数据定义了Nampt在MM生物学中的关键作用，为新型靶向治疗方法提供了基础。（血。2012;120（17）：3519-3529）
Malignant cells have a higher nicotinamide adenine dinucleotide (NAD(+)) turnover rate than normal cells, making this biosynthetic pathway an attractive target for cancer treatment. Here we investigated the biologic role of a rate-limiting enzyme involved in NAD(+) synthesis, Nampt, in multiple myeloma (MM). Nampt-specific chemical inhibitor FK866 triggered cytotoxicity in MM cell lines and patient MM cells, but not normal donor as well as MM patients PBMCs. Importantly, FK866 in a dose-dependent fashion triggered cytotoxicity in MM cells resistant to conventional and novel anti-MM therapies and overcomes the protective effects of cytokines (IL-6, IGF-1) and bone marrow stromal cells. Nampt knockdown by RNAi confirmed its pivotal role in maintenance of both MM cell viability and intracellular NAD(+) stores. Interestingly, cytotoxicity of FK866 triggered autophagy, but not apoptosis. A transcriptional-dependent (TFEB) and independent (PI3K/mTORC1) activation of autophagy mediated FK866 MM cytotoxicity. Finally, FK866 demonstrated significant anti-MM activity in a xenograft-murine MM model, associated with down-regulation of ERK1/2 phosphorylation and proteolytic cleavage of LC3 in tumor cells. Our data therefore define a key role of Nampt in MM biology, providing the basis for a novel targeted therapeutic approach. (Blood. 2012;120(17):3519-3529)